Recognition of RANTES by Extracellular Parts of the CCR5 Receptor
| Autor: | Paolo Lusso, Daniel Häussinger, Luminita Duma, Marco Rogowski, Stephan Grzesiek |
|---|---|
| Přispěvatelé: | Division of Structural Biology,Biozentrum, University of Basel (Unibas), Unit of Human Virology, DIBIT, Perron, Nicolas |
| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Chemokine Magnetic Resonance Spectroscopy Receptors CCR5 Chemokine receptor CCR5 Peptide Plasma protein binding Protein Structure Secondary 03 medical and health sciences Protein structure Structural Biology Escherichia coli Extracellular Humans Receptor Chemokine CCL5 Molecular Biology ComputingMilieux_MISCELLANEOUS 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology [CHIM.ORGA]Chemical Sciences/Organic chemistry 030302 biochemistry & molecular biology [CHIM.ORGA] Chemical Sciences/Organic chemistry Ligand (biochemistry) Protein Structure Tertiary 3. Good health Gene Expression Regulation Models Chemical chemistry Biochemistry Spectrophotometry biology.protein Chemokines Peptides Dimerization Protein Binding |
| Zdroj: | Journal of Molecular Biology Journal of Molecular Biology, Elsevier, 2007, 365 (4), pp.1063-1075 |
| ISSN: | 0022-2836 1089-8638 |
| DOI: | 10.1016/j.jmb.2006.10.040 |
| Popis: | The chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted) is a natural ligand of CCR5, one of the major HIV-1 coreceptors. It is secreted as part of the immune response to human immunodeficiency virus 1 (HIV-1) and inhibits infection by CCR5-dependent (R5) HIV-1 isolates. We have investigated the interaction of RANTES with several peptides derived from the extracellular domains of CCR5 by heteronuclear NMR spectroscopy in aqueous solution. We show that a peptide comprising the first 25 amino acid residues of the CCR5 N-terminal domain and sulfated at the Y10 and Y14 side-chains binds with micromolar affinity exclusively to the monomeric form of RANTES. In contrast to the tight binding of the sulfated peptide, the affinity of the same peptide in non-sulfated form was reduced by more than two orders of magnitude. Peptides derived from the CCR5 extracellular loops ECL1, ECL2 and ECL3 showed only very moderate and mostly non-specific binding. Chemical shift mapping of the interaction of the sulfated N-terminal peptide reveals a contiguous binding surface on RANTES, which comprises amino acid residues of the first beta-strand, the N-loop, the fourth beta-strand and the turns around residues 30 and 40. This binding surface largely overlaps with the dimer interface and is strongly positively charged, providing a rationale for the exclusive binding of the monomer to the peptide and the requirement of the negative sulfate groups at the Y10 and Y14 side-chains. The binding surface also largely overlaps with the segments that were identified previously as crucial for HIV blockade by peptide scanning and mutagenesis studies. These data offer new insights into the structure-function relation of the RANTES-CCR5 interaction and may be helpful for the design of novel HIV-1 inhibitors. |
| Databáze: | OpenAIRE |
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